The present invention relates to a medical treatment for preventing or alleviating the symptoms associated with peripheral neuropathy caused by disease or exposure to a toxic agent, e.g., a chemotherapeutic cytotoxic agent. A reduction or elimination of symptoms is accomplished by administering the drug selegiline.
Peripheral neuropathy is associated with a wide variety of causes, including genetically acquired conditions, systemic disease or exposure to toxic agents. It can manifest itself as a dysfunction of motor, sensory, sensorimotor or autonomic nerves.
Among the most important toxic agents causing peripheral neuropathy are therapeutic agents, particularly those used for the treatment of neoplastic disease. In certain cases, peripheral neuropathy is a major complication of cancer treatment and is the main factor limiting the dosage of chemotherapeutic that can be administered to a patient (Macdonald, Neurologic Clinics 9:955-967 (1991)). This is true for the commonly administered agents cisplatin, paclitaxel and vincristine (Broun, et al., Am. J. Clin. Oncol. 16:18-21 (1993); Macdonald, Neurologic Clinics 9:955-967 (1991); Casey, et al., Brain 96:69-86 (1973)). The identification of methods for preventing or alleviating dose-limiting peripheral neuropathologic side effects would allow higher, and more therapeutically effective doses of these chemotherapeutics to be administered to patients, i.e., the therapeutic efficacy of such chemotherapeutics is typically a function of dose and therefore, increasing dosage provides increased patient survival (Macdonald, Neurologic Clinics 9:955-967 (1991); Oxols, Seminars in Oncology 16, suppl. 6:22-30 (1989)).
Beyond the potential for increasing the effectiveness of cancer chemotherapy, the identification of new methods for treating peripheral neuropathy has obvious value in alleviating the suffering of patients with a wide variety of systemic diseases and genetic conditions. In many cases, progressive neuropathy in the peripheral nervous system can be debilitating or fatal.
Although selegiline has been used extensively as a treatment for Parkinson""s disease, its effectiveness in the prevention or treatment of peripheral nerve dysfunction caused by toxic agents has not been previously known. The present invention is directed to methods which rely upon this surprising and unexpected discovery to reduce or eliminate symptoms associated with peripheral nerve dysfunction.
Selegiline is a potent and selective irreversible inhibitor of monoamine oxidase B (MAO-B) and has been reported to have an action in protecting or rescuing neurons of the central nervous system. For example, in a rat optic nerve crush model, selegiline has been reported to increase the survival of retinal ganglion cells that are at risk of undergoing apoptosis (Buys, et al., Invest. Opthalmol. Vis. Sci. 35:1484 (1994)). Selegiline has also been shown to have a neuroprotective effect in a model of axotomy-induced cell death in spinal motor neurons of the rat (Iwasaki, et al., J. Neurol. Sci. 125:11-13 (1994)) and to enhance neurite outgrowth in a cultured spinal cord neuron (Iwasaki, et al., Annals of Neurology 36:282-283 (1994)). In addition, selegiline has been reported to increase the survival of CNS neurons after exposure to various chemical toxins such as MPP+, kainic acid, or DSP-4 (Gelowitz, et al., Soc. Neurosci. Abstr. 20:246 (1994); Tatton, et al., J. Neurosci. Res. 31:394-400 (1992); Yu, et al., J. Neurochem. 63:1820-1828 (1994)).
With respect to peripheral nerves, selegiline has been reported to be capable of rescuing axotomized rat facial motor neurons (Salo, et al., J. Neurosci. Res. 31:394-400 (1992)). A recently issued patent also suggests that it may be used in stimulating muscle reinnervation in traumatic and non-traumatic peripheral nerve damage (U.S. Pat. No. 5,444,095).
The present invention is based upon the discovery that selegiline can be used to prevent or alleviate the symptoms associated with peripheral neuropathy. In particular, the invention provides a method for protecting a patient from, or treating a patient for, peripheral neuropathy caused by a toxic agent by administering selegiline in an amount sufficient to reduce or eliminate one or more of the symptoms associated with the neuropathy. Typically, the patient will be a human and the toxic agent will be a chemotherapeutic agent, e.g., an agent administered for the treatment of cancer. Although the method is effective for any toxic chemotherapeutic agent causing dysfunction of peripheral nerves, it is most effective for those agents with particularly severe neuropathic side effects such as cisplatin, paclitaxel, vincristine and vinblastin
Any route of delivery may be used for administering the drug, but preferred routes avoid absorption of selegiline from the gastrointestinal tract. Thus, administration transdermally, buccally, or sublingually are among the preferred methods of delivery. The preferred non-oral dose of selegiline is between 0.01 mg/kg per day and 0.15 mg/kg per day, based upon the weight of the free amine. When the oral route of delivery is used, the preferred dosage range is between 0.15 mg/kg per day and 0.75 mg/kg per day based upon the weight of the free amine (typically between about 10 and 50 mg per day).
The present invention is also directed to a method for treating a patient for peripheral neuropathy caused by a genetically inherited condition or systemic disease by administering selegiline in an amount sufficient to reduce or eliminate one or more of the symptoms associated with the neuropathy. As in the case where peripheral neuropathy is due to exposure to a toxic agent, it is preferred that selegiline be administered by a route that avoids absorption of the drug from the gastrointestinal tract. Transdermal, buccal and sublingual routes of administration are among the routes preferred. Again, the dosage of selegiline for non-oral routes of administration should be between 0.01 mg/kg per day and 0.15 mg/kg per day and, when given orally, the preferred dosage range is between 0.15 mg/kg per day and 0.75 mg/kg per day.
The present invention is also directed to a method for treating a patient with cancer by: a) administering a chemotherapeutic agent known to have a toxic effect on peripheral nerves at a dose effective at slowing the progression of the patient""s cancer; b) concurrently administering selegiline to the patient at a dose effective at preventing, reducing or eliminating the peripheral neuropathy associated with the chemotherapeutic agent; and c) increasing the individual or cumulative dosage of chemotherapeutic agent until peripheral neuropathy becomes unacceptably severe. Individual dosage refers to the amount of chemotherapeutic given at a single time, e.g. in a single infusion or injection, whereas cumulative dosage is the total amount of a chemotherapeutic administered over the full course of therapy. Thus, cumulative dosage may be increased by increasing individual dosages, extending the period of therapy or both increasing individual dosages and extending the length of therapy.
The present invention provides the following:
In a method for maximizing the individual or cumulative dose of an anti-neoplastic agent used in the treatment of a patient suffering from a cancer that exhibits a dose-dependent response to said agent, the improvement that comprises the concurrent administration of a selegiline compound in an amount sufficient to permit the individual or cumulative dose of said agent to be maximized without unacceptably severe neurotoxic side effects.
As used herein xe2x80x9cconcurrentxe2x80x9d administration of selegiline and chemotherapeutic means that the drugs are given sufficiently close in time so that their therapeutic effects overlap. The term xe2x80x9cunacceptably severexe2x80x9d refers to side effects that the patient finds intolerable or which the patient""s physician judges to reflect neuropathy that poses so serious a threat to the patient""s health that the dosage of chemotherapeutic agent must be reduced or terminated. Typically, the patient will be a human. The preferred chemotherapeutic agents are cisplatin, paclitaxel, vincristine and vinblastine.
As with the methods discussed previously, selegiline may be administered by any route, but routes that avoid absorption across the gastrointestinal tract, e.g., transdermal, buccal and sublingual routes, are generally preferred. The non-oral dosage of selegiline administered in conjunction with chemotherapeutic agent should, preferably, be between 0.01 mg/kg per day and 0.15 mg/kg per day based upon the weight of the free amine. In general, patients administered selegiline orally should receive a dose of between 0.15 mg/kg per day and 0.75 mg/kg per day.